Abstract 4795: Conditionally active biologics eliminates senescence cells in cancer and aging
Authors: Jian Chen, Christina Wheeler, Jing Wang, Matt Lucas, Haizhen Liu, Kyrie Johnson, Kathryn Woodard, Solmarie Joyner, Cathy Chang, William J. Boyle, Jay M. Short
Journal: Cancer Research (2023)

Abstract The aberrant accumulation of senescent cells in aged and cancerous tissue triggers inflammatory signaling through a senescence-associated secretory phenotype (SASP), promoting aging and tumor progression. Pharmacologically, clearing senescent cells has been shown to have promising effects against cancer and age-related pathologies in preclinical models as well as early human clinical trials. However, current senescent cell elimination strategies are focused on targets that do not distinguish between hyper-inflamed or SASP senescent cells versus relatively non-inflamed senescent cells. In addition, current senescence targets are predominately intracellular with important functions in normal cell population. Therefore, the use of senolytics in the clinic is still limited due to their cytotoxicity to either normal cells or potentially beneficial senescent cells. A more effective senescence cell targeted approach is needed to reduce side effects and increase the efficiency of senescence cell removal or reduction. Conditionally Active Biologics (CAB) technology is a proprietary platform that is unique in its ability to selectively activate in the context of diseased tissues, but not normal tissues, taking advantage of the acidic pH conditions in the inflammatory tumor/aged tissue microenvironment. Senescent cells, similar to tumor cells, are dependent on glycolysis to support molecule synthesis, for hyperinflammation in the case of senescent cells, and thus generate a glycolytic microenvironment (GME), resembling that of the tumor microenvironment. Since our CAB technology is already being deployed in cancer therapy by targeting cell surface markers such as AXL, ROR2, and CTLA4 in clinical studies, we explored whether CAB technology allows selective removal of senescent cells in SASP-associated microenvironments. To identify senescence-specific surface antigens that are broadly and specifically upregulated in senescent cells, we screened our CAB cell surface antigen library in different senescence in vitro models, in vivo aging mouse tissues and a chronic kidney disease mouse model. We have identified several novel senescence markers. Furthermore, in vitro binding assays demonstrated that CAB antibodies targeting these senescence markers have no or very low binding to the target antigen on senescence cells in physiological, alkaline conditions, but have strong binding in glycolytic, acidic SASP conditions. Moreover, we performed antibody-dependent cell-mediated cytotoxicity assays and demonstrated that CAB antibodies were more potent against senescent cells compared to proliferating cells and displayed high selectivity for the glycolytic, acidic microenvironment condition. In conclusion, CAB technology provides a new generation of biologics with an increased safety margin and therapeutic index targeting SASP, acidic senescence cells in cancer and age-related diseases. Citation Format: Jian Chen, Christina Wheeler, Jing Wang, Matt Lucas, Haizhen Liu, Kyrie Johnson, Kathryn Woodard, Solmarie Joyner, Cathy Chang, William J. Boyle, Jay M. Short. Conditionally active biologics eliminates senescence cells in cancer and aging. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4795.